Use of 5-HT(3) receptor antagonists for treating musculoeskeletal diseases

ABSTRACT

The present invention relates to a new use for compounds having 5-HT 3  (serotonin M) receptor antagonist activity, especially tropisetron, for the manufacture of a pharmaceutical composition for the treatment of a non-inflammatory local disease of the musculo-sceletal system, of a local irritation condition of a joint or tendon sheath, or for the local treatment a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition as long as the living pathogen is still present.

[0001] The present invention relates to a new use, in particular a newpharmaceutical use for compounds having 5-HT₃ (serotonin M) receptor, inparticular specific 5-HT₃ receptor, antagonist activity, especially inthe manufacture of a pharmaceutical composition.

[0002] Specifically, the present invention relates to the treatmentsdefined below.

[0003] The 5-HT₃-receptor antagonists comprise a defined and recognisedclass of pharmaceutically active compounds well known in the art andcharacterised, as their name implies, by their pharmacological activity.Various 5-HT₃ receptor antagonist compounds are commercially availableand clinically applied, e.g. in the treatment of emesis.

[0004] In accordance with the present invention it has now surprisinglybeen found that 5-HT₃ receptor antagonists are useful for the treatmentof local non-inflammatory, local irritation-related and localinflammatory disease conditions. This is surprising in that (a) the5-HT₃ receptor antagonists are effective alone; (b) do not only bringpain relief, but also are effective in the treatment of other symptoms,such as effusion, swelling, stiffness and the like, and (c) are locallyeffective, thus not having to rely on systemic administration that mayshow effects e.g. by working via effects on nerves and/or synapses atthe spinal cord. It is also astonishing that relatively high local dosesare both tolerated and effective when local administration is employed.

[0005] Hence, the present invention relates to the use of a 5-HT₃receptor antagonist or of a pharmaceutically acceptable salt of such anantagonist for the manufacture of a pharmaceutical composition for thetreatment of a non-inflammatory local disease of the musculo-sceletalsystem, of a local irritation condition of a joint or tendon sheath, orfor the local treatment a local manifestation at the locomotor apparatusof an inflammatory disease except for a crystal induced arthritis and aliving pathogen induced inflammatory disease condition as long as theliving pathogen is still present for example the treatment of anyprocess, condition, event, or disease as hereinafter described. Inparticular, the present invention provides the use as mentioned beforewhere, in addition to pain at least one further sequela or symptom ofthe local disease, local irritation condition or local manifestation isalleviated, ameliorated or controlled.

[0006] Any 5-HT₃ receptor antagonist can be used in accordance with theinvention. Preferred 5-HT₃ receptor antagonists which may be employed inaccordance with the present invention are:

[0007] A) Ondansetron[1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-IH-imidazol-1-yl]methyl]-4H-carbazol-4-one(cf. Merck Index, twelfth edition, item 6979);

[0008] B) Granisetron[endo-1-methyl-N-(9-methyl-9-aza-bicyclo[3.3.1]non-3-yl)-IH-imidazole-3-carboxamide:(cf. loc. cit., item 4557); and

[0009] C) Dolasetron [IH-indole-3-carboxylic acid (2α, 6α, 8α,9αβ)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester] (cf. loc.cit., item 3471).

[0010] Particular 5-HT₃ receptor antagonists which may be employed inaccordance with the present invention are those of the formula 1 asdefined in European Patent Publication 189002 B1, the contents of whichare incorporated herein by reference, in particular the compound:

[0011] D) Indol-3-yl-carboxylicacid-endo-8-methyl-8-aza-bicyclo[3,2,1]-oct-3-yl-ester, also known astropisetron. (cf. loc. cit., item 9914).

[0012] Further 5-HT₃ receptor antagonists which may be used preferablyin accordance with the present invention are:

[0013] E)4,5,6,7-tetrahydro-5-[(1-methyl-indol-3-yl)carbonyl]benzimidazole (seealso ramosetron, see U.S. Pat. No. 5,344,927);

[0014] F)(+)-10-methyl-7-(5-methyl-1H-imidazol-4-ylmethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one(see also fabesetron, EP 0 361 317); and

[0015] G)[N-(1-ethyl-2-imidazolin-2-yl-methyl)-2-methoxy-4-amino-5-chlorobenzamide(see also lintopride-Chem.-Abstr.-No. 107429-63-0).

[0016] A further 5-HT₃ receptor antagonists which may be used preferablyin accordance with the present invention is

[0017] (H)2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one(see also alosetron, EP 0 306 323).

[0018] 5-HT₃-receptor antagonists may be employed in accordance with theinvention in free or in pharmaceutically acceptable salt form, e.g. asknown in the art, for example, in the case of compounds A) to D) abovein pharmaceutically acceptable acid addition salt form, for example, inthe case of: compound A) the hydrochloride dihydrate; compound B) thehydrochloride; compound C) the mesylate; and compound D) themonohydrochloride. References to 5-HT₃ receptor antagonists collectivelyor individually throughout the present specification and claims areaccordingly to be understood as embracing both free compounds and suchpharmaceutically acceptable salt forms, e.g. as clinically employed, andfurther also solvates, e.g. hydrates, or specific crystal forms of anyof these compounds or salts.

[0019] For use in accordance with the present invention tropisetron(especially in the formulation called NAVOBAN®) is most preferred.

[0020] Thus, the invention relates to the use of a 5-HT₃ receptorantagonist or of a pharmaceutically acceptable salt of such anantagonist for the manufacture of a pharmaceutical composition for thetreatment of a non-inflammatory local disease of the musculo-sceletalsystem, of a local irritation condition of a joint or tendon sheath, orfor the local treatment a local manifestation at the locomotor apparatusof an inflammatory disease except for a crystal induced arthritis and aliving pathogen induced inflammatory disease condition as long as theliving pathogen is still present, where the 5-HT₃ receptor antagonist isselected from the group consisting of ondansetron, granisetron,dolasetron, tropisetron, ramosetron, fabesetron, lintopride andalosetron, which may be used in free form or as a pharmaceuticallyacceptable salt.

[0021] In accordance with the present invention it has now surprisinglybeen found that 5-HT₃ receptor antagonists are useful for the treatmentof certain diseases, processes, conditions or events, namelynon-inflammatory local diseases of the musculo-sceletal system; localirritation conditions of the joints or tendon sheaths; or the localtreatment also of local manifestations at the locomotor apparatus ofinflammatory diseases; such as conditions, processes or events that aredue to trauma (including surgery or preferably accident); overload;posture fault; degenerative processes; conditions subsequent to anotherdisease (including infection, for example viral infection, or tumordiseases); or other conditions that result in irritation of thelocomotor apparatus of the body; meaning especially therapy of therespective non-inflammatory disease, irritation or manifestation assuch, its sequelae or its symptoms, or any combinations of these.

[0022] “Treatment” as used herein includes use for the alleviation,amelioration or control of said diseases, processes, conditions orevents. It also includes intervention for the alleviation, ameliorationor control of the sequelae or symptoms of any one or more of thesediseases, for example degeneration (e.g. of cells, epithelia ortissues), swelling, exudation, effusion or pain, stiffness orinflexibility of joints. In this context the term “treatment” is furtherto be understood as embracing use to reverse, restrict or controlprogression of any specified disease, process, condition event or thelike, including use for disease modifying effect. If any of thementioned diseases, processes, conditions, manifestations or events,especially an inflammatory disease, process, condition, manifestation orevent, is associated with pain, the term “treatment” preferablyencompasses the alleviation, amelioration or control (including temporalor permanent removal) of at least one further sequela or symptom inaddition to pain, such as swelling, effusion, exsudation, lack offlexibility (e.g. due to stiffness and/or lack of flexibility ofjoints), loss of strength or degeneration, more preferably of allsymptoms and most preferably of the total clinical picture of therespective disease, irritation or manifestation. According to thepresent invention, the term “treatment” preferably does not have themeaning of prevention.

[0023] The present invention is in particular applicable to thetreatment of:

[0024] (1) non-inflammatory local diseases of the musculo-sceletalsystem (including a joint or another part of the locomotor apparatus),such as

[0025] (1a) myofasciale syndrome, including myelogelosis, chroniclumbalgia or cervicalgia, for example unspecific or in the context ofdegenerative spinal affections, of static posture fault or malformationof the spine, e.g. cervical syndrome,

[0026] (1b) tendomyosis, tendinosis, insertion tendopathy (e.g.epicondylitis), bursopathy or periarthropathy,

[0027] (1c) overload syndrome of the muscle,

[0028] (1d) syndromes due to the compression of nerves or neuropathy(such as medianus compression syndrome=carpal tunnel syndrome), or

[0029] (1e) algodystrophy (also called neurodystrophy); or

[0030] (2) local irritation conditions (=states of irritation) of ajoint or tendon sheath especially related to

[0031] (2a) a meniscus lesion (e.g. following surgical intervention orpreferably due to damage to the meniscus due to a different cause),

[0032] (2b) arthrosis, such as gonarthrosis,

[0033] (2c) trauma, including accident or post-operative trauma, e.g.after implant or insertion surgery or endoscopy,

[0034] (2d) osteochondritis dissecans, osteonecrosis or jointchondromatosis,

[0035] (2e) or various non-inflammatory rheumatoid diseases, preferablyto the local treatment of one or more of the mentioned diseases under(1) and/or (2); or

[0036] (3) to the local treatment also of a local manifestation at thelocomotor apparatus of an inflammatory disease, such as variousinflammatory rheumatoid diseases (except for crystal induced arthritis(e.g. gout) and except for living pathogen induced diseases as long asthe living pathogen (bacterium, virus or fungus, protozoon, parasite orthe like) is still present), such as

[0037] (3a) chronic polyarthritis (=rheumatoid arthritis), includingjuvenile arthritis or psoriasis arthropathy;

[0038] (3b) sarcoidosis,

[0039] (3c) paraneoplastic syndrome or tumor-induced inflammatorydiseases,

[0040] (3d) turbid effusions,

[0041] (3e) collagenosis, such as systemic Lupus erythematosus,poly-myositis, dermato-myositis, systemic sclerodermia or mixedcollagenosis;

[0042] (3f) postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body), or

[0043] (3g) seronegative spondylarthritis, such as spondylitisankylosans; or further

[0044] (3h) vasculitis.

[0045] In the case of the inflammatory diseases, diseases where a livingpathogen, e.g. a virus, a bacterium, a fungus, a protozoon or a parasiteor the like, is still present, the treatment of must first aim atremoval of the pathogen causative for the disease, before treatment witha 5-HT₃ antagonist is used, as otherwise there is the danger that thecausative pathogen remains intact. Then the mere symptomatic treatmentwith a 5-HT₃ antagonist is contraindicated in order to avoid survival oreven further spread of the causative infection. This is also valid inthe case of combination with an anti-inflammatory glucocorticosteroid asdescribed in the following, as is the proviso that treatment ofcrystal-induced inflammation is excluded.

[0046] The term “locomotor apparatus” refers to any component of themusculo-sceletal system of the body, especially to bony tissue, muscle,tendons, ligaments, joints, cartilage, perichondrium, periosteum,synovial membrane, bursa and the like.

[0047] “Trauma” refers preferably to operative and more preferably totrauma by accident, such as overload, tumble or push.

[0048] The term “local treatment” refers to the treatment with one ormore 5-HT₃ receptor antagonists near or at the site of the manifestationof the disease to be treated, e.g. by intra-muscular injection,intra-articular injection, or any other injection near or at the site ofdisease manifestation (that is, preferably the administration has thegoal to provide for locally higher concentrations of the administeredcompound than would be expected to be achieved by systemicadministration, or the goal is not systemic exposure), preferably withinan area within 20, more preferably 10 cm, still more preferably within 5cm, around the outer limitation of the manifestation of the localdisease, most preferably directly at the affected are or site, e.g. theare or site of symptom manifestation, such as the area of greatest pain,such as an insertion point, a trigger point or a joint, or also in abroader aspect of the invention by local tissue infiltration ortransdermal administration at the site of the manifestation of thedisease, e.g. by means of topical administration e.g. by use of gels,creams or ointments or the like, or by transdermal patch technology. Inthe case of the non-inflammatory diseases mentioned above under (1) and(2), also systemic treatment is possible, e.g. by enteral, especiallyperoral, e.g. by use of tables or capsules, or rectal, e.g. by use ofenemation or suppositories; subcutaneous, intraperitoneal orintra-muscular injection; or infusion is possible. In the case ofintravenous administration bolus injection is preferred. However, localtreatment is preferred in all cases. An advantage of local treatment isthat high efficiency can be reached and that systemic exposure to a5-HT₃ antagonist can be diminished or avoided. One preferred local wayof administration is the intra-articular injection in case of diseases,conditions etc. that relate to joints, e.g. bursopathy or synovitis.

[0049] A preferred example of a local manifestation at the locomotorapparatus of an inflammatory disease is synovial inflammation, forexample, synovitis, including any of the particular forms of synovitisrecited in Dorland's Illustrated Medical Dictionary, 26th edition, pub.W. B. Saunders and Co. at page 1301, as far as it is notcrystal-induced. Such synovial inflammation may for example, beconsequential to or associated with disease, e.g. arthrosis, includingarthritis, e.g. osteoarthritis, rheumatoid arthritis or arthritisdeformans.

[0050] Further preferred local diseases to be treated according to theinvention are those mentioned in the examples.

[0051] From the foregoing it will be noticed that the present inventionis to be understood especially as embracing the treatment, e.g. therapy,of any disease, process, symptom, event or condition as set forth above,for example for the alleviation or control of non-inflammatory localdiseases or irritations or local inflammatory processes or events andthe sequelae associated therewith or consequential thereto, e.g. toalleviate or control joint irritation or effusion; with the proviso thatif pain is treated, then in addition at least one other diseasemanifestation (e.g. effusion, swelling, exudation or degeneration) istreated.

[0052] Preferably the present invention relates to the treatment,especially the local treatment, of a disease as mentioned above under(2) or (3), more preferably one of the diseases mentioned there otherthan algodystrophy and vasculitis.

[0053] In a further aspect it has been found in accordance with thepresent invention that 5-HT₃ receptor antagonists are useful asreplacement therapy for local glucocorticosteroid, e.g. cortisone or thelike, therapy; for example for use in any means of treatment ashereinbefore and hereinafter set forth, e.g. the diseases mentionedunder (2) and (3) hereinabove. The term “replacement therapy” as usedherein is to be understood as embracing both use “as full replacement”,i.e. use instead of glucocorticosteroid therapy, as well as use “aspartial replacement” for glucocorticosteroid therapy, i.e. foradministration together with glucocorticosteroid therapy or as a meansof reducing glucocorticosteroid dosage or to achieve aglucocorticosteroid sparing effect.

[0054] The present invention accordingly provides:

[0055] I. A method of treating any process, condition, event, or diseaseas hereinbefore set forth, in a subject in need thereof, which methodcomprises locally administering an effective amount of a 5-HT₃ receptorantagonist, especially locally at or near the site of the local disease,local irritation condition or local manifestation;

[0056] II. A method of providing replacement therapy forglucocorticosteroid therapy in a subject receiving suchglucocorticosteroid therapy for or in the treatment of any process,condition, event or disease as hereinbefore set forth, which processcomprises locally administering to said subject an effective amount,e.g. a glucocorticosteroid sparing amount, of a 5-HT₃-receptorantagonist; as well as

[0057] III. A method of treating any process, condition, event ordisease as hereinbefore set forth, in a subject in need thereof, whichmethod comprises locally administering an effective amount of a 5-HT₃receptor antagonist together with a glucocorticosteroid.

[0058] Where the term “glucosteroid” is used, this means ananti-inflammatory glucosteroid.

[0059] Where co-administration is practiced as under III above the drugsubstances, i.e. 5-HT₃ receptor antagonist and glucocorticosteroid maybe administered sequentially or simultaneously or substantiallysimultaneously, e.g. employing a fixed combination dosage form. Infurther aspects the present invention also provides:

[0060] IV. A 5-HT₃ receptor antagonist for use in, or for use in themanufacture of a pharmaceutical composition for use in; or the use of apharmaceutical composition comprising a 5-HT₃ receptor antagonist forlocal use:

[0061] a) in the treatment of any process, condition, event or diseaseas hereinbefore set forth;

[0062] b) as replacement therapy for glucocorticosteroid therapy in thetreatment of any process, condition, event or disease as hereinbeforeset forth; or

[0063] c) for co-administration together with a glucocorticosteroid inthe treatment of any process, condition, event or disease ashereinbefore set forth; and/or:

[0064] V. A pharmaceutical dosage form comprising a 5-HT₃ receptorantagonist together with a glucocorticosteroid, especially for the localtreatment of any process, condition, event or disease as hereinbeforeset forth.

[0065] Where under (I) to (V) the term “any process, condition, event ordisease” is used, this term preferably relates to the diseases mentionedunder (1), (2) and (3) above, especially as defined above as beingpreferred.

[0066] The term “locally administering” or “local use” is defined tomean local administration or especially “local treatment” as definedabove, that is, administration at or near the site of thenon-inflammatory disease, irritation condition or local inflammatorydisease condition, in contrast to systemic administration.

[0067] Dosage forms, e.g. in accordance with V above, are to beunderstood as including both fixed-unit-dosage forms, e.g. liquidformulations, comprising both active ingredients together withappropriate pharmaceutically acceptable diluents or carriers, as well astwin delivery systems, packages or the like comprising both activeingredients separately or in separate dosage form, for concommitant orsequential administration.

[0068] The 5-HT₃ receptor antagonists are preferably used in well-knownliquid formulations.

[0069] Utility of 5-HT₃ receptor antagonists in accordance with thepresent invention can be demonstrated in clinical trials carried out inaccordance with standard techniques and methodologies, for example asfollows:

[0070] The following examples are for illustrative purposes and are notintended to diminish the scope of the present invention. Instead oftropisetron, any other 5-HT₃-antagonist, or a pharmaceuticallyacceptable salt thereof, solvate, e.g. hydrate, or crystalline formthereof, especially selected from the group consisting of ondansetron,granisetron, dolasetron, ramosetron, fabesetron, lintopride andalosetron, can be used, or any combination of two or more of these 5-HT₃receptor antagonists or pharmaceutically acceptable salts thereof.

[0071] In the following examples, tropisetron is administered in thestandard formulation of the trademark Navoban® which is available inampoules that contain 2 mg or 5 mg of the active substance, tropisetron.

EXAMPLE 1 Treatment of Synovial Inflammation/Synovitis Consequent toInflammatory Processes

[0072] Trials are performed on 2 patients exhibiting rheumatoidarthritis and severe consequential synovial inflammation as well asmarked pain.

[0073] Two patients exhibiting acute exacerbation of rheumatoidarthritis, one in the shoulder joint, the other in the knee joint, areeach treated once with 2 mg tropisetron administered intra-articularly.In both cases treatment leads to almost complete remission from painwithin a few hours. Both patients are examined over a period of one weekfollowing treatment with tropisetron and are found to be free ofsymptoms.

EXAMPLE 2 Treatment of Synovial Inflammation Following Traumatic orDegenerative Event

[0074] A first patient exhibits repeated exudation from the knee jointconsequential to damage to the meniscus. Prior to the trial the patientreceived injections of glucocorticoid. The patient receives an injectionof 2 mg of tropisetron administered intra-articularly. After 45 min.marked reduction of pain is reported and a major reduction of effusionfrom the knee joint is observed after 5 hours. The patient remains freeof symptoms without further therapy over an observation period of 5days.

[0075] A second patient exhibits damage to the meniscus of the rightknee joint as well as arthritic change leading to synovial irritationwith consequential knee joint effusion. Despite a successfulsynovialectomy prior to trial entry the patient exhibits renewed kneejoint effusion. Two 2 mg doses of tropisetron are administered i.v. overa period of 17 days with 15 injections, one each day with a 2 days pausein therapy. 24 hours after the first i.v. injection, significantimprovement of pain is reported. Following continuation of injections,the patient exhibits as virtually free of symptoms. The exudation fromthe knee joint is completely inhibited without any other medicationwithin 8 days and movement of the knee joint is clearly improved. Theimprovement in condition continues over a further 7 days observationfollowing completion of therapy:

EXAMPLE 3 Treatment of Implant or Insertion Tendopathy

[0076] Three patients exhibiting implant/insertion tendopathy aretreated with tropisetron. The condition treated results in the case ofthe first patient from epicondylitis radialis, in the case of the secondpatient from insertion tendopathy in the area of insertion of thedeltoid muscle and, in the case of the third patient from anenthesiopathy of the Malleolus lateralis. In all three cases,tropisetron is injected once at a dosage of 2 mg in the area of greatestpain, directly into the tissues. In all three cases severity of paindecreases within a period of 60 min. and virtually complete remittal isachieved within 24 hrs., indicating remission from disease remission.Further improvements found after tropisetron injection include increaseof strength and of flexibility of the affected body part.

EXAMPLE 4 Further Examples for the Efficiency of Tropisetron

[0077] Pain is subsequently determined on a visual analogue scale (VAS)that goes from 0 mm (no pain) to 100 mm (strongest pain).

[0078] 4a) Enthesiopathy (Insertion Tendopathy) (with infiltration):

[0079] (i) Female patient, born in 1955; Diagnosis: epicondylitis. Restpain before local injection of tropisetron 30 mm, 7 days later 0 mm.

[0080] (ii) Female patient, born 1947, diagnosis: periarthropathiahumeroscapularis. Rest pain before local injection of tropisetron 85 mm,7 days after local injection 45 mm.

[0081] (iii) Patient born 1953, diagnosis: epicondylitis. Rest painbefore local injection of tropisetron 35 mm, 7 days thereafter 0 mm.

[0082] 4b) Rheumatoid arthritis (intraarticular injection):

[0083] (i) Female patient, born 1942.

[0084] Before injection of Navoban into the right knee joint: rest pain62 mm, pain under exercise 82 mm, bending up to 105°, knee jointcircumference 46 cm. 24 hours later: rest pain 22 mm, pain underexercise 21 mm, bending 105°, knee joint circumference 45 cm. 48 hoursafter treatment: rest pain 0, pain under exercise 5 mm, bending 110°,knee joint circumference 45 cm. 7 days after treatment: rest pain 20 mm,pain under exercise 16 mm, bending up to 145°, knee joint circumference45.4 cm.

[0085] (ii) Female patient, born 1947.

[0086] Before injection of 2 mg Navoban into the left knee joint: restpain 25 mm, pain under exercise 85 mm, bending up to 115°, knee jointcircumference 37.5 cm. 24 hours later: rest pain 8 mm, pain underexercise 58 mm, bending 120°, knee joint circumference 37.5 cm. 48 hoursafter treatment: rest pain 6 mm, pain under exercise 55 mm, bending115°, knee joint circumference 37.5 cm. 7 days after treatment: restpain 5 mm, pain under exercise 59 mm, bending up to 115°, knee jointcircumference 37 cm. Now 5 mg Navoban are injected into the knee joint,7 days later the patient has a rest pain of 0 mm, pain under exercise of33 mm, bending is possible up to 120°, and the knee joint circumferenceis 37.5 mm.

[0087]4 c) Treatment of left knee joint irritation (Morbus Still):

[0088] Patient, 26 year old, Morbus Still diagnosed 1.5 years ago.Despite basic treatment with 15 mg methotrexat per week and 20 mgprednisolone per day, the patient suffers from swelling and overheatingof the left knee joint for the first time in February 1999. Pain at restin the VAS 98 (0-100), pain under strain 70. Obvious articular effusion.Knee joint circumference 44 cm, straightening/bending 0°-10°, 115°. 24hours after an intraarticular injection with 2 mg tropisetron pain atrest in the Visual Analog Scale (VAS) 0, pain under strain 70.Straightening/bending 0°, 0°, 135°, knee joint circumference 41 cm, withsignificant reduction of joint swelling and effusion respectively. 7days later pain at rest in the VAS 0, pain under strain 57,straightening/bending 0°, 0°, 130°, knee joint circumference 40.5 cm.

[0089]4 e) Gonarthrosis:

[0090] Patient, 74 years old, has activated gonarthritis with effusionfor 2 months. Only short-term pain reduction by means of non-steroidalantiphlogistics could be achieved. Following an intra-articularinjection with 2 mg tropisetron, pain at rest after 24 hours on thevisual analog scale for pain (0-100) sinks from 43 to 25, after 2 daysto 13, after 7 days to 10 and in a follow-up check after 17 days to 4.The analog values for pain under strain are 75, 45, 10 and 10,respectively. The effusion is gone after 7 days, as is the overheatingof the knee joint.

EXAMPLE 5 Spinal Syndrome (i.v. Administration)

[0091] Female patient born 1957, diagnosis: cervical syndrome. Beforeinjection of 2 mg trooisetron 68 mm rest pain, 24 hours later 35 mm, atday 7 18 mm.

EXAMPLE 6 Spinal Syndromes (i.v. Administration)

[0092] (i) Cervical Syndrome:

[0093] Female patient born 1957, diagnosis: cervical syndrome. Beforei.v. injection of 2 mg tropisetron 68 mm rest pain, 24 hours later 35mm, at day 7 18 mm.

[0094] (ii) Lumbalgia:

[0095] Patient born 1940, diagnosis: lumbalgia. The patient is injected2 mg Navoban i.v., the rest pain before the injection amounts to 78 mm,the pain under exercise 90 mm, the Schober distance upright/with bendedupper part of the body between the processus spinalis vertebrae ofvertebra 1 and 5 (“Schober” hereinafter) 10/11 cm, the distance fromfingers to ground with bended upper part of the body 32 cm; 24 hourslater, the rest pain is 36 mm, the pain under exercise 43 mm, theSchober 10/12.3, and the finger/ground distance 24 cm; after 48 hours,the rest pain is 28 mm, the pain under exercise 47 mm, the Schober10/12.5, the finger/ground distance 26.5 cm. 7 days after treatment, therest pain is 15 mm, the pain under exercise 22 mm, the Schober 10/13,and the finger/ground distance 22 cm.

[0096] Equivalent results as in the preceding examples are obtainable inequivalent or comparable trials with patients exhibiting similarsymptomatology employing 5-HT₃-receptor antagonists other thantropisetron, for example using any of the 5-HT₃-receptor antagonists A)through C) or E) through H) hereinbefore recited at comparable, e.g.conventional clinical, dose as known in the art. Similar results arealso achievable employing 5-HT₃-receptor antagonists, e.g. tropisetronat doses of the order of 2 mg/day p.o. or by injection or topicalapplication in clinical trials involving subjects exhibiting other localnon-inflammatory or local inflammatory diseases, conditions or symptoms.

[0097] Trials conducted as described above or analogously aredemonstrative of long lasting and disease modifying effects inconditions herein described as well as symptomatic andglucocorticosteroid replacement effect for 5-HT₃ receptor antagonists.

[0098] For use in accordance with the present invention the appropriatedosage will, of course, vary depending on for example the particular5-HT₃ receptor antagonist employed the mode of administration and thenature and severity of the condition to be treated as well as thespecific condition to be treated. In general an indicated single, e.g.daily, dosage will be in the range usually employed for knownindications such as emesis and will typically be from about 0.05 toabout 50 mg per day, more preferably around 1 to 10 mg per day,conveniently administered once or in divided doses up to four times aday or in sustained release form, or used repeatedly after longerintervals, e.g. after some days or weeks, e.g. after 2 days to 4 weeks.In the case of tropisetron an appropriate dosage for administration,e.g. by injection, for example for i.v. application or injection directinto the affected areas, will be of the order of 2 mg per day or 5 mgper day, administered once, sequentially over a sequence of 2 to 20 daysor at intervals of 2 to 5 days to 2 days to 2 weeks.

[0099] For use in accordance with the invention, 5-HT₃ receptorantagonists may be administered by any conventional route in particularenterally, preferably orally, e.g. in the form of tablets or capsules,or rectally, e.g. in the form of suppositories or enemation, or mostpreferably parenterally, e.g. in the form of injectible solutions orsuspensions, e.g. by subcutaneous, intraperitoneal or intra-muscularinjection for systemic administration. Suitable formulations for use inaccordance with the present invention will include any of those as knownand commercially available and clinically employed in the art, forexample the commerically available formulations. Preferably, thecompositions are administered locally, that is, near or at the site ofthe manifestation of the disease to be treated, e.g. by intramuscularinjection, intra-articular injection or any other injection near or atthe site of disease manifestation; in a broader aspect of the invention,also local tissue infiltration or transdermal administration may beconsidered, e.g. by use of gels, creams or ointments or the like, orpreferably by transdermal patches. Dosages for such forms will be of theorder or slightly higher than those used on administration by injection.

1. The use of a 5-HT₃ receptor antagonist or of a pharmaceutically acceptable salt of such an antagonist for the manufacture of a pharmaceutical composition for the treatment of: a) a non-inflammatory local disease of the musculo-sceletal system selected from the group consisting of myofasciale syndrome, tendomyosis, tendinosis, insertion tendopathy, bursopathy or periarthropathy, overload syndrome of the muscle, syndromes due to the compression of nerves or neuropathy and algodystrophy; b) a local irritation condition of a joint or tendon sheath related to a meniscus lesion, arthrosis, trauma, locally osteochondritis dissecans, osteonecrosis or joint chondromatosis, and various non-inflammatory rheumatoid diseases; or c) for the local treatment of a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition as long as the living pathogen is still present, wherein said inflammatory disease being selected from chronic polyarthritis, sarcoidosis, paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid effusions, collagenosis, postinfectious arthritis, seronegative spondylarthritis and vasculitis.
 2. The use according to claim 1, wherein the disease to be treated is a non-inflammatory local disease of the musculo-sceletal system selected from the group consisting of myofasciale syndrome, tendomyosis, tendinosis, insertion tendopathy, bursopathy or periarthropathy, overload syndrome of the muscle, syndromes due to the compression of nerves or neuropathy and algodystrophy.
 3. The use according to claim 1, wherein the disease to be treated is a local irritation condition of a joint or tendon sheath related to a meniscus lesion, arthrosis, trauma, locally osteochondritis dissecans, osteonecrosis or joint chondromatosis, and various non-inflammatory rheumatoid diseases.
 4. The use according to claim 1 for the local treatment of a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition as long as the living pathogen is still present, wherein said inflammatory disease being selected from chronic polyarthritis, sarcoidosis, paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid effusions, collagenosis, postinfectious arthritis, seronegative spondylarthritis and vasculitis.
 5. The use according to claim 1, wherein the 5-HT₃ receptor antagonist is selected from the group consisting of ondansetron, granisetron, dolasetron, tropisetron, ramosetron, fabesetron, lintopride and alosetron, which may be used in free form or as a pharmaceutically acceptable salt.
 6. The use according to claim 5, wherein the 5-HT₃ receptor antagonist is tropisetron.
 7. A method of treating a) a non-inflammatory local disease of the musculo-sceletal system selected from the group consisting of myofasciale syndrome, tendomyosis, tendinosis, insertion tendopathy, bursopathy or periarthropathy, overload syndrome of the muscle, syndromes due to the compression of nerves or neuropathy and algodystrophy; b) a local irritation condition of a joint or tendon sheath related to a meniscus lesion, arthrosis, trauma, locally osteochondritis dissecans, osteonecrosis or joint chondromatosis, and various non-inflammatory rheumatoid diseases; or c) a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition as long as the living pathogen is still present, wherein said inflammatory disease being selected from chronic polyarthritis, sarcoidosis, paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid effusions, collagenosis, postinfectious arthritis, seronegative spondylarthritis and vasculitis, in a subject in need thereof, which method comprises locally administering to said subject an effective amount of a 5-HT₃ receptor antagonist.
 8. A method according to claim 7, wherein the 5-HT₃ receptor antagonist is administered locally at or near the site of the local disease, local irritation condition or local manifestation.
 9. A method according to claim 7 or 8, wherein the 5-HT₃ receptor antagonist is tropisetron.
 10. A 5-HT₃ receptor antagonist or a pharmaceutical composition comprising a 5-HT₃ receptor antagonist for local use in the treatment of: a) a non-inflammatory local disease of the musculo-sceletal system selected from the group consisting of myofasciale syndrome, tendomyosis, tendinosis, insertion tendopathy, bursopathy or periarthropathy, overload syndrome of the muscle, syndromes due to the compression of nerves or neuropathy and algodystrophy; b) a local irritation condition of a joint or tendon sheath related to a meniscus lesion, arthrosis, trauma, locally osteochondritis dissecans, osteonecrosis or joint chondromatosis, and various non-inflammatory rheumatoid diseases; or c) a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition as long as the living pathogen is still present, wherein said inflammatory disease being selected from chronic polyarthritis, sarcoidosis, paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid effusions, collagenosis, postinfectious arthritis, seronegative spondylarthritis and vasculitis.
 11. Tropisetron or a pharmaceutical composition comprising tropisetron for local use according to claim
 10. 